Dual-engineered cartilage-targeting extracellular vesicles derived from mesenchymal stem cells enhance osteoarthritis treatment via miR-223/NLRP3/pyroptosis axis: Toward a precision therapy

上睑下垂 骨关节炎 间充质干细胞 软骨 细胞生物学 软骨细胞 化学 炎症 癌症研究 炎症体 医学 生物 免疫学 病理 解剖 替代医学
作者
Weixuan Liu,Anqi Liu,Xujun Li,Ziyang Sun,Sun Zheng-hua,Yaru Liu,Gang Wang,Dan Huang,Hao Xiong,Shiyang Yu,Xintao Zhang,Cunyi Fan
出处
期刊:Bioactive Materials [Elsevier]
卷期号:30: 169-183 被引量:35
标识
DOI:10.1016/j.bioactmat.2023.06.012
摘要

Osteoarthritis (OA) is the most common disabling joint disease with no effective disease modifying drugs. Extracellular vesicles released by several types of mesenchymal stem cells could promote cartilage repair and ameliorate OA pathology in animal models, representing a novel therapeutic strategy. In this study, we demonstrated that extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hUC-EVs) could maintain chondrocyte homeostasis and alleviate OA, and further revealed a novel molecular mechanism of this therapeutic effect. miR-223, which could directly bind with the 3'UTR of NLRP3 mRNA, was found to be a key miRNA for hUC-EVs to exert beneficial effects on inflammation inhibiting and cartilage protecting. For enhancing the effect on mitigating osteoarthritis, exogenous miR-223 was loaded into hUC-EVs by electroporation, and a collagen II-targeting peptide (WYRGRL) was modified onto the surface of hUC-EVs by genetic engineering to achieve a more targeted and efficient RNA delivery to the cartilage. The dual-engineered EVs showed a maximal effect on inhibiting the NLRP3 inflammasome activation and chondrocyte pyroptosis, and offered excellent results for the treatment of OA. This study provides a novel theoretical basis and a promising therapeutic strategy for the application of engineered extracellular vesicles in OA treatment.
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